Polymeric Drug-Delivery Material, Method for Manufacturing Thereof and Method for Delivery of a Drug-Delivery Composition

ABSTRACT

A method for manufacturing a drug-delivery composition includes providing at least one pharmaceutically active compound, a dry powder comprising at least a polymer, and an aqueous solution. The dry powder, the pharmaceutically active compound and the aqueous solution are mixed to form a paste-like or semi-solid drug-delivery composition, wherein the aqueous solution is added in an amount of less than or equal to twice the total dry mass of the dry powder.

FIELD OF THE INVENTION

The present invention belongs to the field of controlled drug release,particularly to methods for manufacturing drug-delivery compositionsincluding pharmaceutically active substances or compounds, and to thecontrolled delivery thereof into living organisms and tissues fortherapeutic purposes.

BACKGROUND OF THE INVENTION

Most therapeutic dosage forms include mixtures of one or more activepharmaceutical ingredients (APIs) with additional components referred toas excipients. APIs are substances which exert a pharmacological effecton a living tissue or organism, whether used for prevention, treatment,or cure of a disease. APIs can occur naturally, be producedsynthetically or by recombinant methods, or any combination of theseapproaches.

Numerous methods have been devised for delivering APIs into livingorganisms, each with more or less success. Traditional oral therapeuticdosage forms include both solids (tablets, capsules, pills, etc.) andliquids (solutions, suspensions, emulsions, etc.). Parenteral dosageforms include solids and liquids as well as aerosols (administered byinhalers, etc.), injectables (administered with syringes, micro-needlearrays, etc.), topicals (foams, ointments, etc.), and suppositories,among other dosage forms. Although these dosage forms might be effectivein delivering low molecular weight APIs, each of these methods suffersfrom one or more drawbacks, including the lack of bioavailability aswell as the inability to completely control either the spatial or thetemporal component of the API's distribution when it comes to highmolecular weight APIs. These drawbacks are especially challenging foradministering biotherapeutics, i.e. pharmaceutically active peptides(e.g. growth factors), proteins (e.g. enzymes, antibodies),oligonucleotides (e.g. RNA, DNA, PNA), hormones and other naturalsubstances or similar synthetic substances, since many of thesepharmacologically active biomolecules are at least partially broken downby the digestive tract or in the blood system and are subsequentlydelivered in suboptimal dosing to the target site.

Therefore, there is an ongoing need for improved drug-delivery methodsin life sciences, including but not limited to human and veterinarymedicine. One important goal for any new drug-delivery method is todeliver the desired therapeutic agent(s) to a specific place in the bodyover a specific and controllable period of time, i.e. controlling thedelivery of one or more substances to specific organs and tissues in thebody with control of the location and release over time. Methods foraccomplishing this localized and time controlled delivery are known ascontrolled-release drug-delivery methods. Delivering APIs to specificorgans and tissues in the body offers several potential advantages,including increased patient compliance, extending activity, lowering therequired dose, minimizing systemic side effects, and permitting the useof more potent therapeutics. In some cases, controlled-releasedrug-delivery methods can even allow the administration of therapeuticagents that would otherwise be too toxic or ineffective for use.

There are five broad types of solid dosage forms for controlled-deliveryoral administration: reservoir and matrix diffusive dissolution,osmotic, ion-exchange resins, and prodrugs. For parenterals, most of theabove solid dosage forms are available as well as injections(intravenous, intramuscular, etc.), transdermal systems, and implants.Numerous products have been developed for both oral and parenteraladministration, including depots, pumps, micro- and nano-particles.

The incorporation of APIs into polymer matrices acting as a corereservoir is one approach for controlling their delivery. Contemporaryapproaches for formulating such drug-delivery systems are dependent ontechnological capabilities as well as the specific requirements of theapplication. For sustained delivery systems there are two mainstructural approaches: the controlled release by diffusion through abarrier such as shell, coat, or membrane, and the controlled release bythe intrinsic local binding strength of the API(s) to the core or toother ingredients in the core reservoir.

Another strategy for controlled delivery of therapeutic agents,especially for delivering biotherapeutics, is their incorporation intopolymeric micro- and nano-particles either by covalent or cleavablelinkage or by trapping or adsorption inside porous network structures.Various particle architectures can be designed, for instance core/shellstructures. Typically one or more APIs are contained either in the core,in the shell, or in both components. Their concentration can varythroughout the respective component in order to modify their releasepattern. Although polymeric nano-spheres can be effective in thecontrolled delivery of APIs, they also suffer from severaldisadvantages. For example, their small size can allow them to diffusein and out of the target tissue. The use of intravenous nano-particlesmay also be limited due to rapid clearance by the reticuloendothelialsystem or macrophages. Notwithstanding, polymeric micro-spheres remainan important delivery vehicle.

In view of the above, there is a need for improving drug-deliverymethods and compositions.

SUMMARY OF THE INVENTION

According to an embodiment, a method for manufacturing a drug-deliverycomposition is provided. The method includes providing at least onepharmaceutically active compound, a dry powder including at least apolymer, and an aqueous solution; and mixing the dry powder, thepharmaceutically active compound and the aqueous solution to form apaste-like or semi-solid drug-delivery composition, wherein the aqueoussolution is added in a total amount of less than or equal to twice thetotal dry mass of the dry powder.

According to an embodiment, a drug-delivery composition is provided,which includes a paste-like or semi-solid mixture including at least apolymer, a pharmaceutically active compound, and an aqueous solution,wherein the total amount of the aqueous solution in the paste-like orsemi-solid mixture is less than or equal to twice the total dry mass ofthe mixture.

According to an embodiment, a method for delivering a drug-deliverycomposition is provided. The method includes providing a drug-deliverycomposition including a paste-like or semi-solid mixture having at leasta polymer, a pharmaceutically active compound, and an aqueous solution,wherein the total amount of the aqueous solution in the paste-like orsemi-solid mixture is less than or equal to twice the total dry mass ofthe mixture; and applying the drug-delivery composition into a human oranimal body.

Those skilled in the art will recognize additional features andadvantages upon reading the following detailed description, and uponviewing the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a furtherunderstanding of embodiments and are incorporated in and constitute apart of this specification. The drawings illustrate embodiments andtogether with the description serve to explain principles ofembodiments. Other embodiments and many of the intended advantages ofembodiments will be readily appreciated, as they become betterunderstood by reference to the following detailed description. Theelements of the drawings are not necessarily to scale relative to eachother. Like reference numerals designate corresponding similar parts.

FIG. 1 illustrates processing steps of a manufacturing method accordingto an embodiment.

FIG. 2 illustrates processing steps of a manufacturing method accordingto an embodiment.

FIG. 3 shows a photograph of the stable gelatin body obtained accordingto an embodiment and according to the procedure of FIG. 2.

FIGS. 4A and 4B show photographs of water-based formulations ofgelatin-water mixtures according to the procedure illustrated in FIG. 2and described by the experiment of FIG. 3.

FIGS. 5A, 5B, 5C, 5D, 5E, 5F, 5G and 5H show a series of eightphotographs of dry-route formulations (prepared as described in FIG. 2)combining carboxymethylcellulose (CMC) with chitosan.

FIGS. 6A, 6B and 6C show a series of three six photographs of dry-routeformulations according to FIG. 2 combining carboxymethylcellulose withchitosan beginning with (a) acetic acid and (b) plant oil as wettingagents.

FIG. 7 presents antibody release curves from drug-delivery compositionsprepared according to several examples illustrating embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The following language and descriptions of certain preferred embodimentsof the present invention are provided to further an understanding of theprinciples of the present invention. However, it will be understood thatno limitations of the present invention are intended, and that furtheralterations, modifications, and applications of the principles of thepresent invention are also included.

According to an embodiment a drug-delivery composition is manufacturedby providing at least one pharmaceutically active compound, a dry powderincluding at least a polymer, and an aqueous solution. The dry powder,the pharmaceutically active compound and the aqueous solution are thenmixed to form a paste-like or semi-solid drug-delivery composition,wherein the aqueous solution is added in an amount less than or equal totwice the total dry mass of the dry powder. The pharmaceutically activecompound is referred to hereinafter as active pharmaceutical ingredient(API).

For the purpose of this specification, the term “mixing” intends todescribe a mechanical working or a mechanical treatment of thecomponents. For example, mixing can be in the sense of carrying outrepeated cycles of pressing and folding or comparable process stepswhich lead to an intense compression and mixing of the providedwater-deficient or quasi-dry compositions and mixtures. Mixing includes,according to an embodiment, pressing and folding of a water-deficientcomposition including API(s), excipients and an aqueous solution such aswater. An embodiment also includes cold extruding of the composition.

The drug-delivery composition includes polymeric delivery materialsformed from dry mixtures by a process which can include, according to anembodiment, intimate mixing of a dry powder mixture and thencontinuously wetting and mixing the powder in a controlled manner,without intermittent drying steps, to achieve an API-containingsemi-solid material, possessing superior controlled-delivery properties.It is believed, that the step-wise addition of only small amounts of theaqueous solution such as water, a composite liquid, or a solvent withsustained mixing of the components (e.g. algorithmic pressing-foldingcycles) allows for specific molecular interactions by solute shieldinglayers at interfaces, especially in the vicinity of functional groupsand structural elements of the involved macromolecules, which would beotherwise suppressed by self organization or self assembly in freesolution or suspension. Such interactions relate to intra-molecularinteractions of both excipients and involved APIs but also tointermolecular interactions of both excipients and APIs and ofexcipients with APIs.

By slowly hydrating and mixing the solid mixture, it is believed thatAPIs come into better and more-controlled contact with the excipientsdoing the same with each other. This results in the onset of differentinteraction mechanisms, which would otherwise not be triggered. Thesuggested method is especially suitable for formulating biologicalcompounds. Biopolymer-like proteins, peptides, poly- andoligonucleotides are particularly sensitive to changes in theirenvironment and may lose their specific activity more readily thansmall-molecule APIs. Synthetic APIs and excipients mimickingbiomacromolecules may carry both anionic and cationic groups in therelevant medium or may possess different functional groups in variabledensity on a molecular backbone. These molecules, i.e. biopolymers andpolyampholytes are known to have different configurations depending onthe molecular environment, i.e. distinct folding patterns, tertiary andquaternary structures. Since a certain activity may be closely relatedto a certain spatial configuration, these molecules are apt to alteredrelease characteristics when formulated according to the suggestedmethod. Therefore, the approach described herein is believed to have aminimal impact on the natural conformation of the APIs and is thusespecially advantageous for the stable formulation of biotherapeutics bycontrolled release.

The suggested approach combines the benefit of initial thoroughdry-mixing with the controlled-release advantages of polymericmicro-spheres but does not suffer from the disadvantages of any of theseformulations when applied alone.

The matrix formed by the polymer is typically a hydrophilic matrix butcan also include a small amount of hydrophobic substances.

The resulting polymeric drug-delivery materials can be subsequentlytransferred into the final dosage form either directly or after anoptional, later step of forming semi-solid particles, bodies ormicro-particles of desired shape, size and size distribution by means ofcolloid forming techniques and other technological procedures.Remarkably, any solute or dispersant in excess of 200% by weight of theAPIs and involved excipients as well as any intermittent drying orevaporating of solute or dispersant from the semi-solid material, may beavoided in order to reach and to maintain the specific properties of theformed API-excipient complex. According to an embodiment, no additionalsolute is added during formation of the drug-delivery composition sothat the composition does not transform into a more liquid form.According to an embodiment, the drug-delivery composition is not driedbut kept as paste. This ensures that the specific releasecharacteristics can be maintained.

The compositions formed by the methods described herein can maintain thedrug-releasing properties for a prolonged time such as weeks and months.The APIs remain protected in the paste-like or semi-solid mixture sothat their bioavailability can be maintained. If desired, additionalbarrier layers can be formed around the paste-like or semi-solidmixture.

The suggested method is different from other approaches in that thepaste-like or semi-solid composition is formed by addition of a solutionto a dry powder of a polymer, which forms the matrix of the compositioninto which the API is distributed and mixed. According to an embodiment,the paste-like or semi-solid composition is formed by kneading, as anexample of algorithmic pressing-folding cycles.

According to an embodiment, the API is provided as dry pharmaceuticallyactive compound powder. The dry polymer powder is homogeneously mixedwith the dry pharmaceutically active compound to prepare a drypre-powder mixture before the aqueous solution is added. The solutioncan either be added step-wise or continuously. Intensive mechanicalworking such as kneading may be needed for mixing the dry pre-mixturewith the slowly or step-wise added solution to form a paste. It isbelieved that the intense mechanical interaction with the slow orstep-wise addition of the solution results in the specific molecularinteraction between the polymer matrix itself and also between thepolymer matrix and the API and optional excipients as described above.

According to an embodiment, the added amount of the aqueous solution isless than or equal to twice the total dry mass of the dry powdermixture. According to a further embodiment, the added amount of theaqueous solution is less than or equal to the total dry mass of the drypowder mixture.

The processing can include repeated pressing and folding of the mixtureof the dry powder, the pharmaceutically active compound and the aqueoussolution to form the paste-like or semi-solid drug-delivery composition.For example, a small amount of the solution is added to the polymerpowder or the pre-mixtures of polymer and API. The mechanical processingmay start with pressing to bring the mass into a more flat shape andthen folding the mass, for example by a blade or other suitable means.The folded mass is then pressed again. By repeating these procedures adistribution of the solution and APIs throughout the powder mass can beachieved. During this mechanical processing, more solution is added sothat more and more of the powder mass is “wetted” to form a paste. Theaddition of the API to the treated system can occur during all phases ofthe preparation process, and, according to an embodiment, at a latestage after forming an established excipient matrix system. Itguarantees a minimum mechanical/mixture influence on the APIs.

According to an embodiment, the mechanical processing of the mass canalso include other processes such as rolling.

The force acting on the mass may be limited to avoid excessivemechanical impact that might affect the API. According to an embodiment,a pressure of not more than 10⁶N·m⁻² is applied to the mass. Accordingto further embodiments, a pressure of not more than 5×10⁵N·m⁻² isapplied to the mass.

According to an embodiment, the pharmaceutically active compound (API)is dissolved in the aqueous solution before being mixed with the drypolymer powder. The API is not provided as dry component but ascomponent dissolved in the solution. However, since the solution isadded in a limited amount, it is believed that the aforementionedspecific molecular interactions also take place.

According to an embodiment, the dry powder and the aqueous solution aremixed to form a paste-like or semi-solid mass and then thepharmaceutically active compound (API) is added to the paste-like orsemi-solid mass to form the paste-like or semi-solid drug-deliverycomposition. The API can either be added in dry or liquid form such asdissolved in a solution. When adding in liquid form, the amount ofliquid added should be taken into account for the amount of solutionadded to the dry powder to keep the drug-delivery composition inpaste-like or semi-solid form. The solution added to the dry powder andthe solution in which the API is dissolved can be the same or can bedifferent.

According to an embodiment, the API can be provided in particulate formsuch as micro-particles or nano-particles. Suitable particle size rangesare from about 100 nm to about 50 μm, particularly from about 500 nm toabout 30 μm, and more particularly from about 1 μm to about 10 μm.

According to an embodiment, the polymer for the hydrophilic matrix is ahydrophilic polymer that swells when mixed with the aqueous solution.Suitable polymers are polyvinyl alcohol (PVA), polyvinylpyrrolidone(PVP), polyethylene glycol (PEG), gelatin, collagen, alginate, starch,cellulose, chitosan, carboxymethylcellulose, cellulose derivatives,pectin, gum arabic, carrageenan, hyaluronic acid, albumin, fibrin,fibrinogen, synthetic polyelectrolytes, polyethylenimine, acacia gum,xanthan gum, agar agar, polyvinylalcohol, borax, polyacrylic acidsincluding derivatives, protaminsulfate, casein, and derivatives thereof.According to an embodiment, inorganic polymers such as clay and silicacan also be used for the hydrophilic matrix. According to an embodiment,the polymer has a molecular weight of at least 10 kDa. Furthermore,polyampholytes can be used as a polymer component. According to anembodiment, a polymer from the group of biopolymers is used. Accordingto an embodiment, a polymer from the group of hydrogel formingsubstances such as gelatin is used. According to an embodiment, apolymer from the group of polyelectrolyte complex forming substances isused. Such substances typically include two components of oppositecharge selected from two polyelectrolytes of opposite charge and apolyelectrolyte and a small ion of opposite charge such as alginate andcalcium. According to an embodiment, a polymer from the group ofpolyampholytes is used. According to an embodiment, a polymer from thegroup of inorganic gel forming substances is used.

It is assumed that the method as described herein leads to very specificmolecular interactions, which define the release characteristics of thepolymeric drug-delivery composition. Different to macromolecules in freesolution, the amount of the added solution in the method as describedherein is so small that the resulting composition cannot be regarded asfree solution. Typically, the amount of solution is only equal to, oreven only a fraction of, the initial dry powder mass, so that theformulation route is expected to operate along a deficient amount ofdissolving water supporting the intimate contact of all possibleintermolecular interaction spots. This early, intimate, and controlledcontact of the matrix excipients with each other and with APIsestablishes various stabilizing and function-improving or -conservingintra- and intermolecular interactions to obtain a more controlledprocedure. The method as described herein may employ a ratio of the massfraction of aqueous solution to the dry matrix components between 0.1and 2, preferably between 0.3 and 1.2, and most preferably between 0.5and 1. Consequently, the components cannot be considered to becompletely dissolved or dispersed, but should instead be thought of asbinding partners for which the other system components compete. Thus,the medium has to be considered as a partner at the same level as theAPI and the macromolecular excipients. Also, the release mediumconditions have to be taken into account in order to obtain aquantitative estimate of the release kinetics. Ultimately, the energydifference with respect to an ideal thermodynamic equilibrium and thepresence of activation barriers determine the release conditions of theAPI from the formulated structure. This is especially relevant because alower free energy of active binding and lower activation barriers willfavor faster release kinetics.

In the novel approach as described herein, the controlled addition ofliquid (mainly aqueous solutions or water or composite liquid orsolvent) transforms the preparation into a paste- or dough-likeconsistency, which is appropriate for the production of slow releasecompositions. The processes according to one embodiment include mixingof all ingredients in dry form in a first step followed by wetting thesemixtures and adding liquid media in a controlled manner to transform thewetted mixtures into paste-like or semi-solid consistency. Thus, theinteractions of the formulation/fabrication procedures are controlledthroughout the method.

As described herein, composite polymeric delivery materials can beformed by maintaining control over strength and sequence of thedifferent API-excipient interactions from the beginning of the process.Thus, even during the initial dry-powder mixing, the interactions occurunder essentially non-wetted conditions. These interactions are switchedon or off or modified by the step-wise addition of limited amounts ofliquid media such as water, protic solvents (e.g. acetic acid) oraqueous solutions. This approach also helps to minimize the use ofexcipients and water or solvent, since these formulation routes areprocessed under minimal water/solvent conditions. Thus, one aspect ofthe method described herein is the ability to start with maximumconcentration of the API(s). For example, a gelatin gel is stabilized bymore or less hydrophobic spots distributed at a given concentrationthroughout the self-organized gel. The spot concentration depends on thedissolved gelatin concentration. The proposed novel approach increasesthe gelatin stabilizing hydrophobic spot concentration or equivalentlythe material concentration per spot far above this equilibrium value bythe addition of both, low amounts of water and mechanical treatmentovercoming the repulsive barriers for forming the high concentrationstabilizing spots throughout the gel/water mass. Surprisingly, this newconfiguration demonstrates a tremendous stability (meta-stability)created by a driven process as opposed to self-organization orself-assembly.

Independent of the selected route, the precise control of allinteractions between the APIs and excipients is desired in order toachieve successful formulation, even if excipients form membranes thathave to be penetrated by the APIs. Thus, the methods as described hereinstarts with maximum concentrations of both the APIs and the excipientsaccording to an embodiment and subsequently adapt the conditions duringthe process of mixture, structuring, manufacturing, and polymericdelivery material formation up to the essential concentrations in thefinal delivery forms.

According to an embodiment, APIs can be small molecules, peptides,proteins, therapeutic proteins, antibodies, antigens, enzymes, receptorligands, nucleotides or nucleotide analogs, oligonucleotides andoligonucleotide analogs, genes or gene-like species, viruses, virus-likeparticles, sugars or polysaccharides or their analogs, or any otherphysical composition such as living organelles, cells, or tissueconstituents. According to an embodiment, excipients can include almostany member of these same classes of species. They often act as buffer,filler, binder, osmotic agent, lubricant, or fulfill similar functions.Polyampholytes are multiply-charged polymers which bear both anionic andcationic groups in the relevant medium, e.g. in an aqueous solution. Thevarious classes and types of APIs, excipients, polymers, andpolyampholytes are familiar to those skilled in the art of drugdelivery.

According to an embodiment, the excipient can be, for example, a sugarsuch as monosaccharides, disaccharides, oligosaccharides,polysaccharides, or albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin, globulin,polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof.

According to an embodiment, the pharmaceutically active compound can beone or more of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti-TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors), peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), deoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.

According to an embodiment, the drug-delivery composition can be broughtinto an implantable form to form an implantable drug-deliveryformulation with controlled-release kinetics. The bringing into animplantable form can include addition of biodegradable or bioerodiblepolymers. The polymer matrix itself according to the novel proposedapproach can also be comprised of biodegradable or bioerodible polymers.Furthermore, a micro-porous membrane made from ethylene/vinyl acetatecopolymer or other materials for ocular use can be formed around thepaste-like or semi-solid mixture. Further options include use ofbiodegradable polymers for subcutaneous and intramuscular injection,bioerodible polysaccharides, hydrogels. The implantable drug-deliveryformulation can be activated by osmotic pressure, or any other mechanismtested in the past, like vapor pressure or magnetism.

The approach described herein distinguishes from oral formulations suchas tablets, caplets, and pills in that a paste-like or semi-solidcomposition is prepared. Commonly known administered formulations mayinclude powder mixtures. However, they are merely compressed or coatedcompacts produced from thoroughly mixed amorphous or crystallinepowders.

The present invention encompasses not only the use of pure aqueous mediabut can comprise also minor amounts of plant oils or any otherpharmaceutically acceptable solvents or their mixtures. The method andcomposition described herein can use any substance which can exert atherapeutic effect, including small molecules, synthetic or biologicalmacromolecules such as peptides, proteins, oligonucleotides,carbohydrates, and others familiar to one skilled in the art.

The polymeric delivery materials of the present invention can optionallybe labeled with any of a wide variety of agents, which are known tothose skilled in the art. As examples, dyes, fluorophores,chemiluminescent agents, isotopes, metal atoms or clusters,radionuclides, enzymes, antibodies, or tight-binding partners such asbiotin and avidin can all be used to label the polymeric drug-deliverycomposition for detection, localization, imaging, or any otheranalytical or medical purpose. The polymeric delivery composition,particularly the polymer of the matrix, can also optionally be coated orconjugated with a wide variety of molecules in order to modify itsfunction, improve its stability, or further modify the rate of releaseof the API. As examples, the drug-delivery composition can be coatedwith a covalently- or non-covalently-attached layer of a species such assmall molecules, hormones, peptides, proteins, phospholipids,polysaccharides, mucins, or biocompatible polymers such polyethyleneglycol (PEG), dextran, or any of a number of comparable materials. Thewide range of materials, which can be used in this fashion, and themethods for accomplishing these processes, are well known to thoseskilled in the art.

It will also be apparent to one skilled in the art that the variousstarting components such as the polymer powder and the API can befurther manipulated and processed using a wide variety of methods,processes, and equipment familiar to one skilled in the art. Forexample, the dry components can be thoroughly mixed using any of anumber of known methods and equipments, such as trituration with amortar and pestle or blending in a Patterson-Kelley twin-shell blender,before the initiation of the wetting stage. Further a wide variety ofshapes, sizes, morphologies, and surface compositions of thedrug-delivery composition can be formed. For example, micro-particles orcylindrical bodies with different aspect ratios can be prepared by meansof mechanical milling, molding, extruding or similar processes of thepaste-like or semi-solid or even solid wet polymeric material. Theresulting particles can be further treated to prepare them for specificapplications such as e.g. drug delivery systems. As another example, thepolymeric particles and bodies can be immersed into oil such as plantoil for conservation and storage. As yet another example, transformingthe wetted mixture, paste or dough into micro-particles or polymericbodies by means of processes such as drying, rheological methods,grinding, milling, pressure homogenization, molding, and/or other suchwell-established procedures can yield a wide range of final products. Asanother example, the polymeric drug-delivery composition can be squeezedthrough a sieving disk containing predefined pores or channels withuniform pore geometry and diameter by an extrusion process, e.g. in arepeating manner.

According to an embodiment, the paste-like or semi-solid mixturedrug-delivery composition has a modulus of elasticity of at least10⁻⁴N·mm². According to an embodiment, the paste-like or semi-solidmixture drug-delivery composition has a modulus of elasticity of atleast 10⁻³N·mm⁻², and particularly 10⁻²N·mm², and more particularly10⁻¹N·mm².

According to an embodiment, the paste-like or semi-solid mixture has aviscosity of not more than 500 Pa·s, and particularly of not more than300 Pa·s. According to an embodiment, the paste-like or semi-solidmixtures has a viscosity of not less than few mPa·s, for example 100mPa·s, and particularly of not less than 1 Pa·s.

According to an embodiment, the pharmaceutical active compound isprovided as powder containing particles ranging from about 100 nm toabout 50 μm, particularly from about 500 nm to about 30 μm, and moreparticularly from about 1 μm to about 10 μm.

FIG. 1 illustrates processing steps of a manufacturing method accordingto an embodiment. An aspect of this embodiment is that the overallamount of water added is deficient with respect to dissolution of theexcipients. First, the dry polymer powder is mixed together with theAPI, for example, antibodies. In a further process, this dry mixture isgradually wetted and mechanically worked to obtain a paste. It should benoted that the aqueous solution is gradually added to the dry mixturedifferent to other approaches, which gradually add a dry powder to asolution. In further processes, the paste can be further processed toobtain particles of a given size, shape and size distribution. Infurther processes, the thus formed particles can be dried, for exampleby freeze-drying.

FIG. 2 illustrates processing steps of a manufacturing method accordingto an embodiment. The aspect of this embodiment is that the overallamount of water added is deficient with respect to dissolution of theexcipients. The particle formation via quasi-dry conditions in grindingand milling processes are embodiments of the mechanical procedures suchas algorithmic cycles of pressing and folding/mixing.

Similar to the embodiment of FIG. 1, a dry powder is prepared by mixingwith a subsequent wetting of the same. In further processes, mechanicalworking such as grinding or milling is used to form particles from thewetted composition, which exhibit solid-like properties. In furtherprocesses, the surface of the particles is modified to further alter therelease characteristics. In further processes, the solution added to themixture is removed.

In the following, specific examples are described.

Example 1

Dry gelatin (10 g) is mixed with small aliquots (1 g) of water in aseries of consecutive steps under steady kneading up to agelatin-to-water ratio of 2. Continuous kneading/mixing for 3 minutesleads to a single gelatin body of well-defined elasticity but only smallplasticity. The introduction of this gelatin body into water at roomtemperature results in a stable, gelatinous body, which does not swellsignificantly over a period of days and weeks (cp. FIG. 3).

Example 2

Dry gelatin (10 g) is mixed with 5 g of water. In contrast to thepreparation process of FIG. 3 the mechanical kneading was carried outfor a time period of 10 seconds only. The obtained gelatin body ispresented in FIG. 4A right after formulation. The total disintegrationof the gelatin body ten hours after formulation is given in FIG. 4B. Thewater of the beaker is starting to gel and forms a continuous gelatinousbody about 30 hours after formulation.

Example 3

5 ml of water was added to a mixture of 5 g of carboxymethylcelluloseand 5 g of chitosan. This mixture was mechanically kneaded for 3 minutesand the solid body shown in FIG. 5A was formed and suspended in water atroom temperature. This same system was photographed after predefinedperiods of time as presented in FIGS. 5B, 5C, 5D, 5E, 5F, 5G and 5H. Acontinuous swelling process is observed during the first documentationperiod of 42 hours, however, not leading to disintegration of the solidmass. Disintegration was observed with a 10 second treatment of the samecomposition (not shown) as observed in the gelatin system of Example 2(FIG. 4). Further observation of the mechanically treated composition upto 145 hours after preparation demonstrates an increasing tendency ofdisintegration. The stabilization effect via the mechanical treatment isclearly visible during the first 42 hours; however, it is much lessexpressed as compared to the gelatin composition as presented in FIG. 3.

Example 4

Equal amounts of dry carboxymethylcellulose and dry chitosan (5 g each)are mixed with 5 g of acetic acid (pH 3) and a small amount (less than 1g) of plant oil. The mixture is mechanically treated for 3 minutes andformed into a spherical body. It is suspended into water at roomtemperature (FIG. 6A) and observed over time (FIG. 6B, after 4 hours).Despite a clearly visible swelling there is no disintegration during the27 hours observation period (FIG. 6C). The CMC/chitosan system is muchless stable than the gelatin system (EXAMPLE 1). If the system ismechanically treated for only 10 seconds the disintegration of thespherical body after suspension into water at room temperature isstarting more or less directly (not shown) and its behavior is, at leastin principle, comparable to the gelatin system of EXAMPLE 2. The gelatinsystem shows a little more stability.

Example 5

First, a calcium alginate film was prepared by addition of a calciumchloride solution to 1.0 g aqueous alginate gel (2%, 0.01% sodium azide)in a flat bowl. After 10 minutes the resulting film was separated frommold and dried for 2 minutes on white filter paper. Second, 2 mg ofantibody 1 of the type of gamma globulin was placed onto the centre ofthe film. Third, the film was folded together and kneaded by hand for 7minutes forming ultimately a spherical particle. To this particle, 1.0 gof an isotonic sodium chloride solution was added. The release ofantibody 1 was determined spectroscopically by the UV 280 nm methodunder sink conditions (cp. FIG. 7, Example 5). Ultimately we observed avery slow release rate (18.5% after 8.5 weeks).

Example 6

First, a calcium alginate film was prepared by addition of a calciumchloride solution to 1.0 g aqueous alginate gel (2%, 0.01% sodium azide)in a flat bowl. After 10 minutes the resulting film was separated fromthe mold and dried for 2 minutes on white filter paper. Second, 25 mg ofmicro-crystalline cellulose and 50 mg of an aqueous antibody 2 (of thegamma globulin type) solution was placed onto the center of the film.Third, the film was folded together and kneaded by hand for 7 minutesforming ultimately a spherical particle. To this particle 1.2 g of anisotonic sodium chloride solution was added. The release of antibody 2was determined spectroscopically by the UV 280 nm method under sinkconditions (cp. FIG. 7, Example 6). Ultimately we observed a mediumrelease rate of 46% in 9.7 weeks. After 3.7 weeks about 90% of releasedantibody 2 is active.

Example 7

66 mg of an antibody 2 solution (25 mg/ml) was added to 24 mg ofmicro-crystalline cellulose and 90 mg of castor oil. This mixture wasmechanically treated using a glass rod for 1 minute. The resultingproduct was mixed with 1.5 g of an aqueous alginate gel (2%, 0.01%sodium azide) and then dropped into a cold aqueous calcium chloridesolution (18%) under stirring (magnetic stirrer 500 U/min). The obtainedcapsules were separated from suspension and washed two times with doubledistilled water. The resulting alginate capsules were added to 3.0 g ofan isotonic sodium chloride solution (0.01% azide). The release ofantibody 2 was determined spectroscopically by the UV 280 nm methodunder no-sink conditions (cp. FIG. 7, Example 7). This system representsa mixed hydrophilic/hydrophobic system. The resulting release behavioris demonstrating a two-phase characteristic; after a fast release periodof 73% in 2.7 weeks there is a slowing down to another 14% over the next22 weeks. After 25 weeks of release about 93% or the released antibody 2is bio-active as checked by ELISA.

Example 8

200 mg of an antibody 3 (of gamma globulin type) solution (50 mg/ml) wasadded to 80 mg micro-crystalline cellulose and 90 mg of castor oil. Thismixture was mechanically treated using a glass rod for 1 minute. Theresulting product was mixed with 1.0 g of an aqueous alginate gel (2%)and then dropped into a cold aqueous calcium chloride solution (18%)under stirring (magnetic stirrer 500 U/min). The obtained capsules wereseparated from suspension and washed two times with double distilledwater and finally added to 5.0 g of an isotonic sodium chloridesolution. The release of antibody 3 was determined spectroscopically bythe UV 280 nm method under no-sink conditions (cp. FIG. 7, Example 8).Ultimately, we observed a similar behavior as in previous EXAMPLE 7.After about 4 weeks of release about 90% of the released antibody 3 isbio-active as determined by ELISA.

1. A method for manufacturing a drug-delivery composition, comprising:providing at least one pharmaceutically active compound, a dry powdercomprising at least a polymer, and an aqueous solution; mixing the drypowder, the pharmaceutically active compound and the aqueous solution toform a paste-like or semi-solid drug-delivery composition, wherein theaqueous solution is added in an amount less than or equal to twice thetotal dry mass of the dry powder.
 2. The method according to claim 1,wherein the added amount of the aqueous solution is less than or equalto the total dry mass of the dry powder mixture.
 3. The method accordingto claim 1, further comprising: providing the pharmaceutically activecompound as dry pharmaceutically active compound powder; andhomogeneously mixing the dry polymer powder with the drypharmaceutically active compound to prepare a dry powder mixture beforeadding the aqueous solution.
 4. The method according to claim 3, whereinthe dry pharmaceutically active compound powder comprises at least thepharmaceutically active compound and at least one excipient selectedfrom the group consisting of monosaccharides, disaccharides,oligosaccharides, polysaccharides like hyaluronic acid, pectin, gumarabic and other gums, albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin, globulin,polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof.
 5. The method according to claim 1, wherein the aqueoussolution is added step-wise to form the drug-delivery composition. 6.The method according to claim 1, wherein the formation of the paste-likeor semi-solid drug-delivery composition includes repeated cycles ofpressing and folding in an algorithmic manner of the mixture of the drypowder, the pharmaceutically active compound and the aqueous solution.7. The method according to claim 6, wherein the aqueous solution isadded step-wise during pressing and folding.
 8. The method according toclaim 6, wherein the pressing applies a pressure of not more than 10⁶N·m⁻².
 9. The method according to claim 1, wherein the dry powder ismixed at least with a portion of the aqueous solution before the drypharmaceutically active compound is added.
 10. The method according toclaim 1, wherein the pharmaceutically active compound is solved in theaqueous solution before being mixed with the dry powder.
 11. The methodaccording to claim 1, further comprising: mixing the dry powder and theaqueous solution to form a paste-like or semi-solid mass; and adding thepharmaceutically active compound to the paste-like or semi-solid mass toform the paste-like or semi-solid drug-delivery composition.
 12. Themethod according to claim 11, wherein the pharmaceutical active compoundis added as solution.
 13. The method according to claim 1, wherein thepharmaceutical active compound is provided as powder comprisingparticles in a range from about 100 nm to about 50 μm.
 14. The methodaccording to claim 1, wherein the polymer is a hydrophilic polymer thatswells when mixed with the aqueous solution.
 15. The method according toclaim 1, wherein the polymer has a molecular weight of at least 10 kDa.16. The method according to claim 1, wherein the pharmaceutically activecompound is selected from a group consisting of immunoglobulins,fragments or fractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or fragments or fractions thereof, peptides having amolecular mass equal to or higher than 3 kDa, ribonucleic acids (RNA),desoxyribonucleic acids (DNA), plasmids, peptide nucleic acids (PNA),steroids, and corticosteroids.
 17. The method according to claim 1,wherein the pharmaceutically active compound is selected from the groupconsisting of: immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti-TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors) peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.
 18. The method according to claim 1, furthercomprising: forming the drug-delivery composition into an applicableform.
 19. The method according to claim 1, wherein the polymer isselected from the group consisting of, polyvinyl alcohol (PVA),polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), gelatin,collagen, starch, cellulose, chitosan, albumin, fibrin, fibrinogen,pectin, gum arabic and other gums, carrageenan, hyaluronic acid,polyethyleneimine, protamin, therapeutic proteins and peptides, nucleicacids, ribonucleic acids and derivatives thereof
 20. A drug-deliverycomposition, comprising: a paste-like or semi-solid mixture comprisingat least a polymer, a pharmaceutically active compound, and an aqueoussolution, wherein the total amount of the aqueous solution in thepaste-like or semi-solid mixture is less than or equal to twice thetotal dry mass of the mixture.
 21. The drug-delivery compositionaccording to claim 20, wherein the total amount of the aqueous solutionis less than or equal to the total dry mass of the mixture.
 22. Thedrug-delivery composition according to claim 20, wherein the aqueoussolution comprises water and electrolyte.
 23. The drug-deliverycomposition according to claim 20, wherein the paste-like or semi-solidmixture has a modulus of elasticity at least of 10⁻⁴ N·mm⁻².
 24. Thedrug-delivery composition according to claim 20, wherein the paste-likeor semi-solid mixture has a viscosity of at least 100 mPa·s.
 25. Thedrug-delivery composition according to claim 20, wherein thepharmaceutically active compound is selected from the group consistingof immunoglobulins, fragments or fractions of immunoglobulins, syntheticsubstance mimicking immunoglobulins or fragments or fractions thereof,therapeutic proteins, peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, andcorticosteroids.
 26. The drug-delivery composition according to claim20, wherein the pharmaceutically active compound is selected from thegroup consisting of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti TNF-alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors) peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.
 27. A method for delivery of a drug-deliverycomposition, comprising: providing a drug-delivery compositioncomprising a paste-like or semi-solid mixture comprising at least apolymer, a pharmaceutically active compound, and an aqueous solution,wherein the total amount of the aqueous solution in the paste-like orsemi-solid mixture is less than or equal to twice the total dry mass ofthe mixture; applying the drug-delivery composition into a human oranimal body.
 28. The method of claim 27, wherein applying the mixtureinto the human or animal body comprises at least one of: implanting orinjecting the mixture into a human or animal body; intraocular injectingthe mixture into a human, or animal body; subcutaneous injecting themixture into a human, or animal body; intramuscular injecting themixture into a human, or animal body; intraperitoneal injecting themixture into a human, or animal body; intravenously injecting themixture into a human, or animal body; administration of the mixture intoa human or animal body by inhalation or intranasal application;intravenously injecting the mixture into a human or animal body; andadministration of the mixture into a human or animal body by inhalationor intranasal application.